Study of RNA-lipid Particle (RNA-LP) Vaccines for Recurrent Pulmonary Osteosarcoma (OSA)

The investigators have shown that intravenous administration of tumor mRNA loaded lipid particles (LPs) localizes primarily to lung, transfect antigen presenting cells (APCs) and lead to an activated T cell response for induction of anti-tumor immunity. In contrast to other formulations, RNA-LPs recruit multiple arms of the immune system (i.e. innate/adaptive), and remodel the systemic/intratumoral immune milieu, which remain potent barriers for vaccine, cellular, and checkpoint inhibiting immunotherapies. After only a single RNA-LP vaccine, the bulk of systemic and intratumoral dendritic cells (DCs) in mice display an activated phenotype; these activated DCs (harvested from tumors) expand antigen specific T cell immunity. In immunologically resistant pulmonary osteosacroma murine tumor models (i.e. K7M2), RNA-LPs induce robust anti-tumor efficacy in settings where immune checkpoint inhibitors (i.e. anti-PD-L1 therapy) do not confer therapeutic benefit. We have already demonstrated safety of RNA-LPs in acute/chronic murine toxicity studies, and in client-owned canine trial.

In this study, we will investigate the safety and immunologic activity of RNA-LP vaccine in patients with recurrent pulmonary osteosarcoma.

Study Overview

• Status: Not yet recruiting
• Conditions: Pulmonary Osteosarcoma
• Intervention / Treatment: Biological: RNA-LP vaccine

• Study Type: Interventional
• Enrollment (Estimated): 43
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Shannon Alford, MPH; Phone Number: (352) 273-8146; Email: PMO@cancer.ufl.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 39 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age < 39 years.
• Histopathologically proven recurrent pulmonary osteosarcoma.
• Must be eligible for thoracotomy (Arms 1 and 2 only).
• Patient must have been enrolled on a screening consent and have had sterile collection of tumor material in a manner suitable for RNA extraction, amplification, and loading of lipid particles (LPs).
• Patients must have recovered from the effects of surgery, biopsy, postoperative infection, and other complications.
• Karnofsky Performance Status (KPS) or Lansky Performance Status (LPS) ≥ 60.

• Bone Marrow:

  1. ANC (Absolute neutrophil count) ≥ 1,000µl (absent treatment)
  2. Platelets ≥ 100,000/µl (absent treatment for at least 3 days)
  3. Hemoglobin > 8 g/dL

• Renal:

  1. BUN ≤ 25 mg/dl
  2. Creatinine ≤ 1.7 mg/dl

• Hepatic

  1. Bilirubin ≤ 2.0 mg/dl
  2. ALT ≤ 5 times institutional upper limits of normal for age
  3. AST ≤ 5 times institutional upper limits of normal for age
• Signed informed consent. If the patient's mental status precludes his/her giving informed consent, written informed consent may be given by the legally authorized representative per institutional policy.
• For subjects of childbearing potential (SOCBP), negative urine or serum pregnancy test at enrollment.
• SOCBP must be willing to use acceptable contraceptive methods to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug.
• Subjects with partners of childbearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 24 weeks following the last dose of study drug.

Exclusion Criteria:

• HIV, Hepatitis B, CMV, or Hepatitis C seropositive.
• Known active infection or immunosuppressive disease.

• Known severe, active co-morbidity, defined as follows:

  • Unstable angina and/or congestive heart failure requiring hospitalization.
  • Unstable cardiac arrhythmias, abnormalities, or transmural myocardial infarction within the last 6 months.
  • Acute bacterial or fungal infection requiring intravenous antibiotics
  • Chronic Obstructive Pulmonary Disease exacerbation or other known respiratory illness requiring hospitalization or precluding study therapy
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects.
  • Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.
  • Patients with autoimmune disease requiring medical management with immunosuppressants.
  • Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy.
  • Known active connective tissue disorders such as lupus or scleroderma that, in the investigator's opinion, place the patient at high risk for radiation toxicity.
  • Pregnancy or subjects of childbearing potential and their partners who are sexually active and who are unwilling or unable to use an acceptable method of contraception for the entire study period; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
• Subjects must not be pregnant or breast-feeding.
• Subjects who require systemic corticosteroids above physiologic doses or not weaned to physiologic dosing within 1 week of scheduled vaccination.
• Subjects who are receiving any other investigational agents or who have been treated on any other therapeutic clinical protocols within 30 days prior to study entry.
• Subjects who are unwilling or unable to receive treatment and undergo follow-up evaluations at the enrolled Sunshine Consortium treatment site.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: RNA-LP vaccine

Biological: RNA-LP vaccine; All subjects will receive two doses of RNA-LP vaccine every two weeks and then once monthly for 12 months afterward. Subjects on the phase 1 portion of the study will be assigned to receive either 0.01 mg/kg mRNA encapsulated in 0.15 mg/kg LPs (dose level -1), 0.02 mg/kg mRNA encapsulated in 0.3 mg/kg LPs (dose level 0), 0.04 mg mRNA encapsulated in 0.6 mg/kg LPs (dose level +1), 0.08 mg mRNA encapsulated in 1.2 mg/kg LPs (dose level +2) following a 3 + 3 design. All subjects on the Phase II portion will receive the maximum tolerated dose determined in the phase I portion of the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose	Determine the maximum tolerated dose of RNA-LP vaccine.	14 months
12 month event-free survival	Determine if RN-LP vaccine therapy extends 12 month event-free survival. Event-free survival is defined as the time from start of treatment to either disease progression or death, whichever occurs first.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival	Determine the event-free survival in patients with recurrent pulmonary oseteosarcoma receiving RNA-LP vaccine. Event-free survival is defined as the time from start of treatment to either disease progression or death, whichever occurs first.	3 years
Overall survival	Determine the overall survival in patients with recurrent pulmonary oseteosarcoma receiving RNA-LP vaccine.	3 years

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: The V Foundation for Cancer Research
• Investigators: Principal Investigator: John Ligon, MD, University of Florida

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2024
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: December 13, 2022
• First Submitted That Met QC Criteria: December 13, 2022
• First Posted (Actual): December 21, 2022

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: April 16, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: immunotherapy; vaccines; pulmonary osteosarcoma; RNA-LP
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Osteosarcoma
• Other Study ID Numbers: OCR43060 (Other Identifier: University of Florida)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No